Introduction and background
Nearly 60 years ago, early experimental studies on the hemodynamic and renal effects of dopamine were carried out by investigators at the Emory University, in Atlanta. In 1963, Goldberg and his co-investigators from this group published the results of a study that evaluated the effect of dopamine infusion in four patients with severe congestive cardiac failure. They observed a natriuretic effect and improved urine output, although the effect was inconsistent and appeared to be dose-dependent (1). A year later, the same team of investigators evaluated the effect of dopamine in nine healthy volunteers and six patients with congestive cardiac failure. Similar to the findings of the preceding study, they observed a natriuretic effect. Besides, the cardiac output, measured by indocyanine green injection, increased in normal subjects. The increase in cardiac output was also associated with an increase in the glomerular filtration rate and the renal plasma flow. The authors proposed that dopamine has a unique, salutary effect on renal blood flow compared to other catecholamines (2).
Several years later, Hollenberg et al. studied the effect of dopamine infusion on twelve healthy volunteers who were being evaluated as potential kidney donors. Dopamine was administered at 3 mcg/kg/min; selective renal arteriography was carried out to assess the renal vascular response. There was no change in the arterial blood pressure at this dose; however, an increase in the renal cortical blood flow was observed, secondary to vasodilatation. This response appeared to be dose specific. A lower dose did not alter the renal blood flow; a higher dose resulted in an increase in the blood pressure without any further increase in the blood flow. They concluded that at a dose of 3 mcg/kg/min, dopamine acted as a renal cortical vasodilator and improved blood flow, without any change in the hemodynamic parameters. They went on to propose that this dose-specific effect of dopamine may enable reversal of conditions that cause renal vasoconstriction and improve renal function (3).
The favorable effects noted in normal subjects and animal studies led to a profusion in the use of dopamine over the next several decades as a catecholamine with a distinctive renal protective effect. Dopamine infusion was considered the magic bullet that would kick-start the failing kidneys, especially in patients with underlying heart failure. The presumed favorable effect of “renal dose” dopamine, was attributed to its selective effect on the dopaminergic receptors in the kidneys. In a low dose of 0.5–2.5 mcg/kg/min, stimulation of the dopaminergic receptors and improved renal blood flow was considered to occur, followed by beta receptor stimulation between 2–5 mcg/kg/min, and alpha-adrenergic effects at higher doses. These dose-dependent effects were largely confined to human volunteers and animals (4) and was never tested in critically ill patients with multiorgan dysfunction.
By the 1990s, questions were raised, and concerns expressed regarding the dopamine-specific effect on renal blood flow. Furthermore, adverse effects were noted, including tachycardia, arrhythmias, and myocardial ischemia. A 1994 editorial suggested that the beneficial renal protective effect attributed to dopamine remained an unfulfilled dream (5). Besides, a randomized controlled trial of 37 normovolemic patients following major vascular surgery did not reveal any effect on the urine output, serum creatinine level, or the creatinine clearance (6), leading to fervent calls put a stop the use of dopamine as a renal protective agent (7).
Against the background of continued widespread use, even in the face of no robust supporting evidence, the ANZICS-CTG (Australian and New Zealand Intensive Care Society Clinical Trials Group) investigators carried out a multi-center placebo-controlled RCT of low-dose dopamine infusion in critically ill patients who were at risk of acute renal failure.
Population and design
The ANZICS-CTG dopamine study was carried out between March 1996 and April, 1999 in 22 ICUs in Australia and one in Hong Kong. Patients were randomized to receive dopamine infusion or placebo. Randomization was stratified according to the participating center.
Inclusion criteria
Patients who met two or more criteria of the systemic inflammatory response syndrome (SIRS) over a 24-hour period were screened. At least one indicator of early renal dysfunction had to be present – a mean urine output <0.5 ml/kg for ≥4 hours, a rise in the serum creatinine level to >150 μmol/l (1.7 mg/dl), or a rise in the serum creatinine level by >80 μmol/l (0.9 mg/dl) in <24 hours, not related to rhabdomyolysis.
Excluded
The study excluded patients younger than 18 years of age, those with acute renal failure in the preceding 3 months, transplanted kidneys, those who received dopamine infusion during the current hospital admission, and patients with a baseline creatinine level of >300 μmol/l (3.39 mg/dl). Patients in whom dopamine could not be administered for >8 hours according to clinician judgment and those who were considered unsuitable for renal replacement therapy were also excluded.
Intervention
Dopamine was infused in a dose of 2 mcg/kg/minute using a syringe pump or a volumetric infusion pump.
Control
Normal saline was administered as placebo in indistinguishable syringes or infusion bags.
Common management
The dopamine or placebo infusion was continued until renal replacement therapy was commenced, or after resolution of renal dysfunction and the SIRS response for a period of at least 24 hours. The infusion was also stopped if a serious adverse event occurred.
Sample size
The authors assumed that dopamine infusion would reduce the peak serum creatinine level, the chosen primary outcome, by 20%. After two planned interim analyses, the treatment effect was revised to a 25% decrease in the peak creatinine level with dopamine. A final sample size of 300 patients provided 90% power with an alpha level of 0.05.
Results
A total of 467 patients were screened; 328 were randomized after exclusions – 163 were assigned to receive dopamine and 165, to placebo. In the final analysis, 161 patients were included in the dopamine arm and 163 in the placebo arm.
Baseline characteristics
Patients in the dopamine and placebo groups had similar severity of illness at baseline (mean APACHE II score of 21 in both groups). The number of patients in shock (58% vs. 63%) and on mechanical ventilation (86% vs. 87%) were also similar. Dopamine was infused for mean duration of 113 hours compared with 125 hours for placebo. After randomization, low-dose dopamine was infused for a mean of 113 hours and placebo was infused for a mean of 125 hours.
Outcomes
Creatinine and urea levels
The peak creatinine level, the primary outcome, was similar in the dopamine and placebo groups (245 ± 144 vs. 249 ±147 μmol/l). The rise in creatinine from baseline was also similar (62 ± 107 μmol/l vs. 66 ± 108 μmol/l). The peak serum urea levels and the rise from baseline were also similar.
Urine output
The urine output rose progressively in both groups of patients after commencement of the infusion. The urine output after 24 and 48 hours of infusion was significantly higher in both groups compared to baseline. The increase in urine output was partly due to the administration of loop diuretics to 90 patients in each group. The dose of frusemide administered was similar in both groups.
Secondary outcomes
The mean duration of mechanical ventilation was similar in the dopamine and placebo groups (10 vs. 11 days). The duration of ICU stay (13 vs. 14 days) and hospital stay (29 vs. 33 days) was also similar. Arrhythmias were common in both groups and were mostly supraventricular arrhythmias or atrial fibrillation. ICU survival was similar in the dopamine and placebo groups (67% vs. 64%); survival to hospital discharge was also similar (57% vs. 53%). Renal replacement therapy was performed in 35 patients in the dopamine group (22%) compared with 40 in the placebo group (25%); the difference was not statistically significant.
Adverse events
Arrhythmias were observed in seven patients in each arm and led to cessation of the infusion.
Study conclusion
The ANZICS study did not identify any impact of dopamine on the peak serum creatinine level, the primary outcome, compared with placebo infusion. No difference was observed in clinical outcomes following the infusion of dopamine is patients at high risk of acute renal failure. The study confirmed the lack of beneficial effect of the so called “renal dose” of dopamine in critically ill patients who were at risk of renal failure.
Strengths
The strongpoints of the study included its randomized controlled design and double blinding, with an adequate sample size to evaluate the primary outcome. The study included critically ill patients who were at high risk of renal failure in whom dopamine was hypothesized to improve outcomes. The multicenter design also provided generalizability.
Limitations
The peak serum creatinine level as the primary outcome measure may be debatable; it could be argued that clinical outcomes including mortality may have been more relevant. A possible dopamine-related protective effect in patients with normal renal function at baseline could not be ruled out. Would a higher dose of dopamine (compared to a fixed dose) produce a beneficial impact? However, the aim of the study was specifically to evaluate the use of low-dose dopamine considering the purported effect on the renal blood flow specifically at this dose. Would dopamine impart beneficial effects among patients who are not critically ill, but nevertheless are at risk of renal dysfunction? The study could not answer this question, being confined to patients admitted to the ICU. Although the hospital mortality was high (42%), it was lower than predicted by the severity score at baseline. The effect of other vasoactive drugs, e.g., norepinephrine, on outcomes could not be discerned; however, such evaluation is rarely feasible in real-world practice. The use of loop diuretics, although similar in both groups, may also have impacted outcomes.
Later studies
Nearly a decade after publication of the ANZICS dopamine study, De Backer et al. compared dopamine with norepinephrine as first-line vasopressor in patients with shock, aiming to restore blood pressure (8). This large RCT included 1679 patients, with 858 randomized to receive dopamine and 821 to norepinephrine. Alternate, open label vasopressors were permitted if blood pressure could not be maintained. The 28-day mortality was similar in both groups of patients. The incidence of arrhythmias was significantly higher with dopamine compared with norepinephrine. Contrary to traditional belief, dopamine use was associated with significantly higher 28-day mortality in the subgroup of patients with cardiogenic shock.
Avni et al. performed a systematic review with meta-analysis to assess the safety and efficacy of vasopressors in septic shock (9). The review included 3,544 patients from 32 trials. Norepinephrine use was associated with a significantly lower mortality compared with dopamine in this meta-analysis [RR 0.89 (95% CI 0.81-0.98)]. The risk of major adverse events including cardiac arrhythmias was also lower with norepinephrine compared with dopamine.
These studies further underlined the lack of evidence of a favorable effect of dopamine on renal function or other important clinical outcomes. The Surviving Sepsis Guidelines also recommend norepinephrine as the vasopressor of choice in septic shock (10).
Summary
Historically, dopamine was considered to impart beneficial effects on renal function, attributed to its effect on the dopaminergic receptors in the kidneys at low doses. Dopamine infusion was found to exert a natriuretic effect and improve the urine output; however, this effect was largely confined to normal human volunteers and in animal studies. The findings from these experimental studies led to decades of dopamine use for its presumed “renal-protective” effect, especially in patients with congestive cardiac failure, who were at high risk of renal dysfunction. However, the salutary effect on renal function was never tested in a large clinical trial including critically ill patients who were at high risk of acute kidney injury. The findings of the ANZICS dopamine trial established beyond doubt that the favorable effects attributed to low-dose dopamine do not translate to a measurable improvement in renal function, or impact clinical outcomes among critically ill patients. Subsequent studies have corroborated these findings. Furthermore, adverse events may be higher with the use of dopamine compared with norepinephrine. The unequivocal findings from these studies have confined the use of dopamine as a renal-protective agent to a handful of ardent believers.
References
1. Goldberg LI, Mcdonald RH, Zimmerman AM. Sodium diuresis produced by dopamine in patients with congestive heart failure. N Engl J Med. 1963 Nov 14;269:1060–4.
2. Mcdonald RH, Goldberg LI, Mcnay JL, Tuttle EP. Effect of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J Clin Invest. 1964 Jun;43(6):1116–24.
3. Hollenberg NK, Adams DF, Mendell P, Abrams HL, Merrill JP. Renal vascular responses to dopamine: haemodynamic and angiographic observations in normal man. Clin Sci Mol Med. 1973 Dec;45(6):733–42.
4. Dasta JF, Kirby MG. Pharmacology and therapeutic use of low-dose dopamine. Pharmacotherapy. 1986;6(6):304–10.
5. Vincent JL. Renal effects of dopamine: can our dream ever come true? Crit Care Med. 1994 Jan;22(1):5–6.
6. Baldwin L, Henderson A, Hickman P. Effect of postoperative low-dose dopamine on renal function after elective major vascular surgery. Ann Intern Med. 1994 May 1;120(9):744–7.
7. Thompson BT, Cockrill BA. Renal-dose dopamine: a siren song? Lancet Lond Engl. 1994 Jul 2;344(8914):7–8.
8. De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779–89.
9. Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis. PloS One. 2015;10(8):e0129305.
10.Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021 Nov;49(11):e1063.
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